5278
MARYE. CIIAI,MERS AND GENNADY M.KOSOLAPOE'F
OMPA Synthesis with a Stoichiometric Amount of Triamido Phos hate.-A mixture of 55 g. of tetramethyldiamidophospforyl chloride, 38.5 g. of hexamethylphosphoramide, and 19.6 g. of triethyl phosphate in the mole ratio of 3:2:1 was heated with agitation a t 155'. The released gas was absorbed in ethanol and ideiitified as ethyl chloride. Its amount was determined by weighing the reaction mixture repeatedly as the reaction progressed. According to equation e a total of 20.8 g. of ethyl chloride should be formed. The amount actually released as a function of time was: 1 hr., 86.5%; 2 hr., 91.4%; 3.5 hr., 95.4%; 4.5 hr., 95.4%. The reaction mixture was then heated to a temperature of 130' under a pressure of 15 mm. in order to remove volatile components still dissolved in the mixture. The clear, dark-brown oil obtained weighed 93.3 g. (theory 92.3 g.). In a Darallel run of eaual size the molecular weight of the reactioi mixture as a *function of time was determined. I t was: start, 189; 1 hr., 265; 2 hr., 272; 3.5 hr., 295; 4.5 hr., 296 (through 286.3). From the second run two additional samples were taken after a reaction time of 3.5 and 4.5 hours, respectively, and tested insecticidally. Their activity was found t o be the same as that of a material prepared according t o equation a. The reaction mixture from the first run was then separated by molecular distillation (boiling range 75 to 120' under a pressure of 1 .O to 0.5 mm.). It left a residue of 34 g. of an amidopolyphosphate product which could not be identified. The distillate had a weight of 56 g. and was analyzed by infrared. I t was found to consist of 77% OMPA and 22% hexaniethylphosphoramide. The total amount of OMPA formed was, therefore, 43 g. and represented a yield of 46.7%. The triamidophosphate recovered amounted to 32.0% of the quantity originally used. This was due to the equilibrium character of the synthesis method. OMPA Synthesis in the Presence of an Excess of Trimidophosphate.-A mixture of 24.5 g. of tetramethyldiamidophosphoryl chloride plus 26 .O g. of hexamethylphosphoramide plus 8.75 g. of triethyl phosphate was heated four hours with agitation a t 155'. The reaction mixture contained the components of the mole ratio of 3:3:1. A total of 8.0 g. of ethyl chloride was released, representing
VOl. 75
only 87% of the theoretical quantity due t o the solubility of CZHbC1 in the triamidophosphate. The crude reaction mixture was then concentrated by heating to a pot temperature of 140' under a pressure of 20 mm. The distillate obtained weighed 13 g. and contained according to infrared analysis 90% triamidophosphate and 10% OMPA. The clear, dark brown oil residue weighed 37 g.; its analytical data compared in the following way with pure OMPA: Reaction product
p, : 1 N, % Mol. wt. d14 ?&'D
21.6 18.7 288 1.1632 (20 ") 1,4655 (20 ")
Pure OMPA
21.64 19.57 286.3 1.1360 (25 ") 1.4620 (25')
This material was now purified by molecular distillation, which yielded a distillate of 31 g. and 5 g. of a polyphosphate residue. Infrared analysis of the distillate showed the presence of 88% OMPA and 12% triamidophosphate. The boiling point of the pure OMPA was found to be 119-120' (0.65 mm.). The total yield of OMPA was, therefore, 1.3 g. in the f i s t distillate (vacuum concentration) plus 27.3 g. in the second distillate (molecular distillation). This quantity represented 69.6% of the theoretical yield. -4 mixture of tetramethyldiamidophosphorylchloride with hexainethylphosphoramide, as necessary for the synthesis described, can be prepared from dimethylamine and phosphorus oxychloride. Thus, the synthesis of OMPA from POCIS, dimethylamine and ethyl phosphate is possible by a two-step process.
Acknowledgment.-The author is indebted to Drs. A. W. Baker, Ch. W. Young and L. E. Streeter for analyses and to E. E. Kenaga for insecticidal tests reported in this paper. MIDLAND, MICHIGAN
[CONTRIBUT~ON FROM THE Ross CHEMICAL LABORATORY, ALABAMAPOLYTECHNIC INSTITUTE 1
The Synthesis of Amino-substituted Phosphonic Acids. 111' BY MARYE. CHALMERS AND GENNADY 1L.I. KOSOLAPOFF RECEIVED JUNE 1, 1953 The interaction of dialkyl phosphites, ammonia and aldehydes was employed for the synthesis of the following dialkyl phosphonates which contain JLII amino group on the first carbon atom : diethyl and dibutyl or-aminobenzylphosphonates, diethyl a-aminoethylphosphonate, diethyl a-aminopropylphosphonate, diethyl p-methoxybenzyl-a-aminophosphonate, diethyl p-hydroxybenzyl-a-aminophosphonate,diethyl o-hydroxybenzyl-a-aminophosphonateand diethyl B-phenylethyla-aminophosphonate. The esters were converted to the free aminophosphonic acids, which were characterized. Additional details concerning the preparation of aminomethylphosphonic acid were obtained.
In continuation of our work on the synthesis and the determination of properties of phosphonic acids that contain an amino group in the molecule we examined the Mannich-type reaction which takes place between dialkyt phosphites, carbonyl compounds and ammonia, a reaction which was reported recently by Kabachnik and Medved in several examples involving ketones as the carbonyl compounds. The reaction can be summarily represented by the equation (RO)nP(O)H 4- NHa 4- R'COR' + (RO)zP( 0)CR'R'NHf
Kabachnik and Medved report rather low yields of ( I ) Paper 11, THISJOURNAL, 70, 1283 (1948). (2) bf. I. Kabachnik and T. Ya. Medved, Doklady ARad. Mauk S.S.S.R., 88, No. 6. 689 (1952).
the products, but the method has advantages over other possible procedures. Of particular interest to us is the fact that the method produces derivatives that carry the amino group in position adjacent to the phosphono group, thus yielding a number of compounds that are structurally analogous to the common naturally occurring amino acids. We applied the above reaction to several aliphatic and aromatic aldehydes with satisfactory results. The esters of the amino acids, that were formed in the primary reaction, were characterized either as such or as the hydrochlorides. The esters were then converted to the free amino acids (Kabachnik and Medved dealt primarily with the esters only), which were characterized in the usual way. Thus, seven aminophosphonic acids in the form of race(3) G.M. Kosolapoff, THISJOURNAL, 69, 2112 (1947).
Nov. 5, 1953
SYNTHESIS OF AMXNO-SUBSTITUTED PHOSPHORXC ACIDS
5279
mic (DL) mixtures were obtained. The work on hydrochloride by precipitation with aniline from dry ethanol,' the yield of the acid rises to 87%. resolution of the racemates is in progress. Anal. Calcd. for CsHloOaNP: P, 22.30; N, 10.07. The rather low yields of the aminophosphonates Found: P, 22.52; N, 10.3. can be fairly substantially improved over those rea-Aminoethylphosphonic Acid.-Acetaldehyde (4.4 g.) ported by Kabachnik and Medved if anhydrous and 13.8 g. of diethyl phosphite, placed in a chilled steel ammonia and the aldehyde are premixed in alcohol autoclave, were mixed with a saturated solution of dry solution. Passage of ammonia into a mixture of ammonia in 100 ml. of absolute ethanol and the mixture heated for 8 hr. a t 100'. Distillation gave 6.3-7.8 g. the aldehyde and the dialkyl phosphite, in alcohol was (3543%) of diethyl a-aminoethylphosphonate, b.p. 74' solution, generally gave lower yields. 1.0224. a t 6 mm., b.p. 70-73" at 3 mm., ~ O 1.4150, D Anal. Calcd. for CaHl6O*NP: P , 17.13; N, 7.73; M R , 44.72. Found: P, 17.2; N, 7.82; M R , 44.3. a-Aminobenzylphosphonic Acid.-Freshly distilled benThe ester was hydrolyzed as above and the free acid was zaldehyde (10.6 9.) and 19.4 g. of dibutyl phosphite were isolated through the lead salt procedure. After recrystalliplaced into a stainless steel autoclave. To this mixture zation from water there was obtained a 72% yield of awas added a solution of dry ammonia in 100 ml. of absolute aminoethylphosphonic acid in the form of colorless plates, ethyl alcohol (saturated a t 0") and the autoclave was heated for 10 hr. a t 100'. The cooled reaction mixture was evap- map.above 340'. Anal. Calcd. for C2HaOaNP: P, 24.80; N, 11.20. orated t o dryness, the residue was taken up in 1: 1 mixture of absolute ethanol and diethyl ether, and dry hydrogen Found: P, 24.69; N, 11.31. p-Methoxybenzyl-cu-aminophosphonicAcid.-*-Anisaldechloride was passed into the solution. The yellowish precipitate of the hydrochloride of the dibutyl ester of the de- hyde, b.p. 245-248', prepared by a modified Gattermann sired acid was filtered off and recrystallized from dioxane, reaction' (13.6 g.), in 100 ml. of absolute ethanol was satyielding 6.0 g. (18%) of di-n-butyl a-aminobenzylphospho- urated with dry ammonia a t 0' in a steel autoclave and the nate hydrochloride, m.p. 147-148'. Kabachnik and Medved solution was mixed with 13.8 g. of diethyl phosphite. gave m.p. 149O.* If the product is crystallized from the After heating for 8 hr. a t 100' the reaction mixture was least volume of water, a 28% yield of pure product is ob- evaporated to dryness, the residue was taken up in 1: 1 mixture of dry ether and ethanol, and treated with dry hydrogen tained. Diethyl phosphite gave somewhat better results. The chloride. The colorless precipitate of diethyl p-methoxyreaction of 13.8 g. of diethyl phosphite, 10.6 g. of benzalde- benzyl-a-aminophosphonate hydrochloride was recrystalhyde and 100 ml. of ethanol saturated with ammonia, carried lized from water. The pure product, obtained in 10.4 g. out as above, gave 8.7 g. (31%) of diethyl a-aminobenzyl- (333,) yield, formed X-shaped crystals and melted at 205208 . phosphonate hydrochloride, which melted a t 159-160", after crystallization from water. Kabachnik and Medved Anal. Calcd. for C12H2104NPC1: P, 10.01; N, 4.52; gave m.p. 158-159°.2 C1, 11.29. Found: P , 10.13; N, 4.11; C1, 11.45. Anal. Calcd. for CllHl~O~NPCl:N, 5.01; P , 10.47; The ester was hydrolyzed and the free acid was isolated C1, 12.48. Found: N, 5.17; P , 10.64; C1, 12.16. by the aniline procedure. The acid, obtained in 89% yield, The hydrochlorides of either ester (5-6 9.) were readily formed cross-shaped crystals which melted a t 215-218'. hydrolyzed by refluxing overnight with 100 ml. of concenAnal. Calcd. for CaH1204NP: P , 14.28; N, 6.45. trated hydrochloric acid. After evaporation to dryness, Found: P , 14.41; N, 6.51. the residue was taken up in 100 ml. of water and the solution p-Hydroxybenzyl-cu-aminophosphonicAcid.-Duplication was treated, while hot, with lead oxide (PbO) which was of the above reaction with 6.1 g. of p-hydroxybenzaldehyde added gradually until the solution became alkaline to litmus. and 6.9 g. of diethyl phosphite gave 0.52 g. (3.5%) of diThe solids were filtered off and were washed with much hot ethyl p-hydroxybenzyl-cu-aminophosphonatehydrochloride, water, until the filtrate was free of chlorides. The lead which resinified at 175'. salt was suspended in water and the suspension was treated If the aldehyde (6.1 g.) in 100 ml. of absolute ethanol was with hydrogen sulfide. The lead sulfide was removed by saturated with dry ammonia a t near 0' and the mixture filtration and the filtrate evaporated. The residue of crude treated with 6.9 g. of diethyl phosphite, the usual procea-aminobenzylphosphonic acid was recrystallized from dure gave 4.1 g. (28%) of the above product. water, yielding 64-65% of the pure acid, which melted a t Anal. Calcd. for C11Hlo04NPC1: P , 10.60; N, 4.78; 271-273". Kabachnik and Medved2 give m.p. 272"; C1, 11.81. Found: P, 10.62; N, 4.35; C1, 11.69. Kosolapoff' gives m.p. 273'. ester was hydrolyzed and the free acid was isolated ilnal. CaIcd. for C7H1003NP: P , 16.84; N, 7.48. byThe the aniline procedure in 85% yield. The acid formed Found: P, 16.95; X, 7.61. colorless cross-shaoed crvstals,. m.D. - 150-152'. a-Aminopropylphosphonic Acid.-Propionaldehyde (29.0 Anal. Calcd. for C7H;o04NP: P , 15.69; N, 6.93. Found: g.) was placed into the stainless steel autoclave which was chilled to 0 " . Absolute ethanol (100 ml.) was saturated P, 15.82; N, 6.98. o-Hydroxybenzyl-a-aminophosphonicAcid.-The second with dry ammonia a t 0' and the solution was added to the aldehyde. Diethyl phosphite (69.0 g.) was added to the procedure, given above for the p-isomer, yielded 26% of diethyl o-hydroxybenzyl-cu-aminophosphonatehydrochloride, mixture and the autoclave was heated for 8 hr. at 100'. The cooled reaction mixture was distilled in vacuo, yielding which melted above 310' after crystallization from water. 35.2 g. (36%) of diethyl a-amino-n-propylphosphonate, Anal. Calcd. for CI1HlgOdNPCl: P, 10.60; N, 4.78; b.p. 47-49' a t 3.1 mm. Repetitions of the reaction gave C1. 11.81. Found: P, 10.71; N, 4.62; C1, 11.73. 29% and 32% yields. The ester was hydrolyzed and the free acid was isolated Modified procedure, mentioned in the Introduction, gave by means of the aniline procedure. The product formed better results. cross-shaped crystals after recrystallization from water; it Propionaldehyde (.5.X g ) in 50 ml. of absolute ethaiiol resinified a t 180'; yield 85%. was chilled to 0' and dry ammonia was passed into the soluAnal. Calcd. for C7HloO&P: P , 15.69; N, 6.93. tion until the latter was saturated. The resulting cold solution was added slowly to 13.8 g. of diethyl phosphite Found: P, 15.54; N, 6.89. ,%Phenylethyl-cu-aminophosphonicAcid.-Phenylacetalcontained in a steel autoclave, precooled to approximately 0'. The mixture was then heated for 8 hr. at 100" and the dehyde was obtained in 73% yield by hydrogenation of phenreaction mixture yielded on distillation 10.9 g. (56%) of the ylacetyl chloride.6 The aldehyde (2.0 9.) in 50 ml. of absolute ethanol was saturated at nearly 0' with ammonia in desired ester, b.p. 45-47' a t 2.6 mm., nmD 1.4080, a glass liner of a n autoclave, the solution was mixed with 0.9798. Anal. Calcd. for C7H1sOsPU'P: P , 15.89; N , 7.18; M R , (4) A. I. Vogel, "A Textbook of Practical Organic Chemistry," 49.34. Found: P , 16.0; N, 7.10; AIR, 49.1. Longmans, Green & Co., New York, N. Y.,1948,p. 671. The ester was hydrolyzed and the acid was isolated, as ( 5 ) "Organic Reactions," Vol. 4, John Wiley and Sons, he., New described above, in 74% yield. The acid forms colorless York, N. Y..1948,p. 362; K. W. Rosemund and F. Zetzsche, Bcr., plates, m.p. above 350'. If the acid is obtained from its 64, 425 (1921).
Experimental Part
ARMIGER H. SOMMERS AND SHAWN E. AALAND
5280
2.4 g. of diethyl phosphite dnd heated for 8 hr. a t 100". The reaction mixture yieMed 1.4 g. (31%) of diethyl pp k y l e t h y l - CY - aminophosphonate hydrochloride, which formed colorless needles, m p 230-232', after crystallization from water. 4nal. Calcd. for Cl~H210~NPCl:P, 10.56; N, 3 77; C1, 11.89. Found: P, 10.42; N, 4.46; C1, 11.93. The ester was hydrolyzed and the free amino acid was isolated by the aniline method. The acid, obtained in 83% yield, formed cross-shaped crystals which melted a t 225227'. A n d . Calcd. for C8H1203NP:P, 15.42; N, 6 97 Found: P, 15.50; N, 7.06. Aminomethylphoephanic Acid.-This compound was prew r e d according to Chavannee in order that a more convenient method of isolation be explored. B r ~ ~ m e t h y l p h t h a l ~(100 i d e g.) and 54.6 g. of triethyl phosphite were heated at 150-160° until the evolution of ethyl bromide ceased. The residue was refluxed for 12 hr. with 100 ml. of 48% hydrobromic acid and phthalic acid was filtered from the cooled solution The filtrate was evaporated to dryness, tdken up in 100 ml. of dry ethanol and the clear solution treated with aniline until it became .(6) V Chavanne, Birll S O ~chrin , France, 16, 771 (1948)
1701.
xi
slightly acid to congo red. The precipitated wid was taken up in water, neutralized with sodium hydroxide and steam-distilled to remove traces of aniline. The solution was acidified to litmus with hydrochloric acid and treated with a saturated solution of lead acetate. The precipitate was thoroughly washed with hot water and the suspension was treated with hydrogen sulfide. Evaporation of the filtrate and recrystallization of the resulting crude acid from water gave a 58% yield of pure aminomethylphosphonic acid, m.p. above 300'. A n d . Calcd. for CH603NP: P, 27.92; S , 12.61. Found: P, 28.10; N,12.73. The Mannich reaction with dialkylamines and dialkyl phosphites has been also reported by Fields.? Two products of this reaction that were necessary for our studies were prepared in good yield by the procedure given by Fields. Since Fields does not cite any physical properties of his products other than boiling points, the following may be of interest: diethyl N,N-diethylaminomethylphasphonate, b.p. 128-130' a t 15 mm., nZoD 1.3848, d"* 0.8779; dib.p. 94ethyl a-(N,N-diethylamino)-isopropylphosphonate, 95' a t 15 mm., n% 1.4190, dm4 0.9256. ~
~ ~ _ _
_.
r7) P:. K. Fields, 'THIS
JOURNAL.
74, 1.528 (1952).
AUBURS, ALA.
[CONTRIBUTION FROM ABBOTT LABORATORIES
The Reaction of 1 ,S-Dibromopentane with o-Substituted Anilines. The Synthesis of 1-Arylpiperidines BY ARMIGER H. SOMMERS AND SHARON E. AALAND RECEIVED JUNE 22, 1953 The reaction of o-toluidine, o-anisidine, o-chlaroaniline or a-naphthylamine with 1,5-dibromopentane yielded an N-( osubstituted-phenyl)-piperidine (IV) as the principal product, although a small amount of an N,N'-diarylpentamethylentdiamine (11)was sometimes isolated as by-product. 2,6-Dimethoxyaniline behaved similarly; however, the only product obqmed with 2,6-&imethylaniline is N,N'-bis-(2,&dimethylphenyl)-pentamethylenediamine (VII), a result which indicates &eqter steric hindrance by the two methyl groups. m-Anisidine gave N-nz-methoxyphenylpiperidinefrom this reaction, dnd dpethylation of the methoxyphenylpiperidines provided the corresponding aminophenols. Two of these were converted t o dimethylcarbamyl esters, and quaternary salts were prepared and tested as anti-curare agents.
Soon after von Braun described a synthesis of I ,5-dibromopentane2 this compound was used by Scholtz and Wassermann3 for the synthesis of mor $-substituted N-phenylpiperidines (I) from the corresponding substituted anilines. An o-substituent, they reported, prevented the formation of a piperidine ring and led to the formation of an N,N'diarylpentamethylenediamine (11).
$3.3
R meta or para
R \-
K
/
2 --NHn
I
+ Br(CH2)5Br + R
R
11
This conclusion was accepted by von Braun4and reference to it is made, without comment, in more (1) Presented bebre the Organic Division of the American Chemical Society, Chicago, Ill., September, 1953. (2) J. von Braun, Ber.. 87, 3210 (1904). (3) M. Scholtz and E Wassermann, i b d , 40, S i 2 (1907) (4) I
\1811
recent publications,5 but there seems to be no other experimental evidence to indicate that sufficient steric hindrance exists in o-substituted anilines to prevent N,N-disubstitution. To the contrary, two paperssJ take exception to physical data presented for N-tolylpiperidines prepared by this reaction, and other results have been reported which are not compatible with those of Scholtz and W a ~ s e r m a n n . ~ Cerkovnikov and Prelog8 obtained N-arylpiperidines by the action of 3-dimethylamino-1,5-dibromopentane upon o-toluidine and a-naphthylamine. This cannot be reconciled with the failure of 1,sdibromopentane to undergo similar ring formation, unless the reactions are significantly different. A possible intermediateg in the former alkylation is l,l-dimethyl-2-(~-bromoethyl)-azetidinium bromide, which was prepared by Cerkovnikov and Prelog,s and which yields a substituted piperidine upon treatment with aniline. These authors con-
Br.iii!l. rbri
4 1 2 l i b it'lrlYi
(6) J. Houben, "Die Methoden der Organischen Chemie," Third Edition, Vol. 4, George Thieme, Leipzig, 1941, (Edwards Brothers, Inc.. Ann Arbor, Mich., 1944), p. 580; A. A. Morton, "The Chemistry of Heterocyclic Compounds," McGraw-Hill Book Co., Inc., New York, N. Y.,1946, p. 232. (6) A. N. Bourns, H. W. Embleton and M. K. Hansuld, C Q ~J.. Chem., SO, 1 (1952). (7) J. viin Braun, B r r . , 40, 3Y22 (1907). ( 5 ) I
